Prenatal Diagnosis of Mosaic Tetrasomy 18p in a Case without Sonographic Abnormalities

Small supernumerary marker chromosomes (sSMC) are still a major problem in clinical cytogenetics as they cannot be identified or characterized unambiguously by conventional cytogenetics alone. On the other hand, and perhaps more importantly in prenatal settings, there is a challenging situation for counseling how to predict the risk for an abnormal phenotype, especially in cases with a de novo sSMC. Here we report on the prenatal diagnosis of a mosaic tetrasomy 18p due to presence of an sSMC in a fetus without abnormal sonographic signs. For a 26-year-old, gravida 2 (para 1) amniocentesis was done due to consanguineous marriage and concern for Down syndrome, based on borderline risk assessment. Parental karyotypes were normal, indicating a de novo chromosome aberration of the fetus. FISH analysis as well as molecular karyotyping identified the sSMC as an i(18)(pter->q10:q10->pter), compatible with tetrasomy for the mentioned region. Cordocentesis was done due to normal sonography and the results from amniocentesis were confirmed. The parents opted for pregnancy termination and post mortem examination now noted, low anterior hairline, large philtrum, low-set posteriorly rotated malformed ears with prominent antihelix, lower limbs joint contracture and digital anomalies, including long and narrow toes with clinodactyly of the 1st and 5th toes and postaxial polydactyly of one hand. De novo i(18p) can be considered as a special case in the sense that the major relevant phenotypes mentioned for it, i.e. feeding difficulties, abnormalities in muscle tone and developmental/mental retardation, cognitive and behavioral characteristics, recurrent otitis media and seizures, are mostly postnatal. This emphasizes the necessity to determine the nature of a de novo euchromatic marker chromosome, especially in cases with normal ultrasound result and the suitability of a cordocentesis in order to better predicting the pregnancy outcome and parental counseling.

Small supernumerary marker chromosomes (sSMC) are still a major problem in clinical cytogenetics as they cannot be identified or characterized unambiguously by conventional cytogenetics alone. On the other hand, and perhaps more importantly in prenatal settings, there is a challenging situation for counseling how to predict the risk for an abnormal phenotype, especially in cases with a de novo sSMC. Here we report on the prenatal diagnosis of a mosaic tetrasomy 18p due to presence of an sSMC in a fetus without abnormal sonographic signs.
For a 26-year-old, gravida 2 (para 1) amniocentesis was done due to consanguineous marriage and concern for Down syndrome, based on borderline risk assessment. Parental karyotypes were normal, indicating a de novo chromosome aberration of the fetus. FISH analysis as well as molecular karyotyping identified the sSMC as an i(18)(pter->q10:q10->pter), compatible with tetrasomy for the mentioned region. Cordocentesis was done due to normal sonography and the results from amniocentesis were confirmed. The parents opted for pregnancy termination and post mortem examination now noted, low anterior hairline, large philtrum, low-set posteriorly rotated malformed ears with prominent antihelix, lower limbs joint contracture and digital anomalies, including long and narrow toes with clinodactyly of the 1 st and 5 th toes and postaxial polydactyly of one hand. De novo i(18p) can be considered as a special case in the sense that the major relevant phenotypes mentioned for it, i.e. feeding difficulties, abnormalities in muscle tone and developmental/mental retardation, cognitive and behavioral characteristics, recurrent otitis media and seizures, are mostly postnatal. This emphasizes the necessity to determine the nature of a de novo euchromatic marker chromosome, especially in cases with normal ultrasound result and the suitability of a cordocentesis in order to better predicting the pregnancy outcome and parental counseling. Isochromosome 18p has an approximate prevalence of 1/140,000 to 180,000 live births and thus is a relatively rare chromosomal aberration; still it appears to be one of the most commonly observed isochromosomes (5,6). It has been proposed that isochromosome 18p arises as a result of two independent events: nondisjunction and centromeric misdivision based on the fact that all cases reported thus far have been monocentric (7-9). As major mechanisms, it is suggested that nondisjunction occurs during maternal meiosis II followed by centromeric misdivision, implying that maternal age may play a role in the formation of the isochromosome (1,9).

Case report
A 26-year-old, gravida 2 (para 1) was referred for amniocentesis at 16 weeks of gestation because of her own personal request; the latter was justified by a concern for Down syndrome based on    (Fig. 2).

Discussion
Among supernumerary isochromosomes, those derived from the short arm of chromosome 18 are the ones most commonly observed (2,3).
Tetrasomy 18p-syndrome due to sSMC-formation is de novo in the overwhelming majority of the reported patients, like in the here presented one.
However, exceptionally there are also familial cases (3,10). The latter supports again what was mentioned before, i.e. i(18p)-cases may have a high clinical variability (3,5,6). This makes the de novo occurrence of an i(18p), especially when being present as a mosaic state, a considerable challenge in prenatal settings. In the case of i(18p) this could be even more substantial from this point of view that as we saw, sonographic signs and expected phenotypes can be so mild that they are overlooked.
In addition, the fact that the present case had no remarkable echocardiogram made the problem worse, although this fits well to the fact that cardiac anomalies are present in only 12.3% of such patients (5,6).
For comparable cases with normal sonography a cordocentesis has been regarded as a useful step to get further insights into the fetal situation. Chen et al. reported in a prenatally detected mosaic tetrasomy 18p, a cytogenetic discrepancy between amniocytes (mosaic) and cord blood lymphocytes (no i(18p) detectable) (11). After genetic counseling the pregnancy was carried to the term and a normal male baby was delivered. In another case Jung et al. did cordocentesis at 32 weeks of gestation because of congenital heart disease, IUGR, cardiomegaly, and imperforate anus observed in prenatal ultrasound, with tetrasomy 18p detected in karyotyping and FISH analysis (12).
What can be implied from our case and the other cases is that, de novo i(18p) can be considered as a special case in the sense that the major relevant phenotypes mentioned for it, i.e. feeding difficulties, abnormalities in muscle tone and developmental/ mental retardation, cognitive and behavioral characteristics, recurrent otitis media and seizures, are mostly postnatal (5,6). This emphasizes the necessity to determine the nature of a de novo euchromatic marker chromosome, especially in cases with normal ultrasound result, and highlights that studying a second fetal tissue (e.g. cordocentesis) can help the parents to better understand the situation they are in.